Tyrosine kinase inhibitors have often been reported to treat early-stage hormone-receptor-positive breast cancers. In particular, neratinib has shown positive responses in stage I and II cases in women with HER2-positive breast cancers with trastuzumab. In order to augment the biopharmaceutical attributes of the drug, the work designed endeavors to explore the therapeutic benefits of neratinib in combination with naringenin, a phytoconstituent with reported uses in breast cancer. A UPLC-MS/MS method was developed for the simultaneous estimation of neratinib and naringenin in rat plasma, while imatinib was selected as the internal standard (IS). Acetonitrile was used as the liquid extractant. The reversed-phase separation was achieved on a C18 column (100 mm × 2.1 mm, 1.7 µm) with the isocratic flow of mobile phase-containing acetonitrile (0.1% formic acid) and 0.002 M ammonium acetate (50:50, % v/v) at flow rate 0.5 mL·min−1. The mass spectra were recorded by multiple reaction monitoring of the precursor-to-product ion transitions for neratinib (m/z 557.138→111.927), naringenin (m/z 273.115→152.954), and the IS (m/z 494.24→394.11). The method was validated for selectivity, trueness, precision, matrix effect, recovery, and stability over a concentration range of 10–1280 ng·mL−1 for both targets and was acceptable. The method was also assessed for greenness profile by an integrative qualitative and quantitative approach; the results corroborated the eco-friendly nature of the method. Therefore, the developed method has implications for its applicability in clinical sample analysis from pharmacokinetic studies in human studies to support the therapeutic drug monitoring (TDM) of combination drugs.